A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

TY - JOUR

T1 - A glucagon-like peptide-1 receptor agonist reduces intracranial pressure in a rat model of hydrocephalus

AU - Botfield, Hannah F

AU - Uldall, Maria S

AU - Westgate, Connar S J

AU - Mitchell, James L

AU - Hagen, Snorre M

AU - Gonzalez, Ana Maria

AU - Hodson, David J

AU - Jensen, Rigmor H

AU - Sinclair, Alexandra J

N1 - Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

PY - 2017/8/23

Y1 - 2017/8/23

N2 - Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na+- and K+-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.

AB - Current therapies for reducing raised intracranial pressure (ICP) under conditions such as idiopathic intracranial hypertension or hydrocephalus have limited efficacy and tolerability. Thus, there is a pressing need to identify alternative drugs. Glucagon-like peptide-1 receptor (GLP-1R) agonists are used to treat diabetes and promote weight loss but have also been shown to affect fluid homeostasis in the kidney. We investigated whether exendin-4, a GLP-1R agonist, is able to modulate cerebrospinal fluid (CSF) secretion at the choroid plexus and subsequently reduce ICP in rats. We used tissue sections and cell cultures to demonstrate expression of GLP-1R in the choroid plexus and its activation by exendin-4, an effect blocked by the GLP-1R antagonist exendin 9-39. Acute treatment with exendin-4 reduced Na+- and K+-dependent adenosine triphosphatase activity, a key regulator of CSF secretion, in cell cultures. Finally, we demonstrated that administration of exendin-4 to female rats with raised ICP (hydrocephalic) resulted in a GLP-1R-mediated reduction in ICP. These findings suggest that GLP-1R agonists can reduce ICP in rodents. Repurposing existing GLP-1R agonist drugs may be a useful therapeutic strategy for treating raised ICP.

U2 - 10.1126/scitranslmed.aan0972

DO - 10.1126/scitranslmed.aan0972

M3 - Journal article

C2 - 28835515

SN - 1946-6234

VL - 9

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 404

M1 - eaan0972

ER -